This project is studying transformation by human and animal papillomaviruses. Certain genital human papillomaviruses (HPV), types 6 and 11, are frequently associated with benign condylomas but rarely with carcinomas, while other types, HPV16 and 18, are less frequently detected in condylomas but are the predominate types detected in genital carcinomas. Since the viral E6 and E7 genes are selectively retained and expressed in the carcinomas, we have undertaken a comparative analysis of these genes from the presumed low risk and high risk types. We have determined that the in vitro transforming activities of E6 and E7 from HPV6 are lower than those of E6 and E7 from HPV16 and 18; these results have also been correlated with lower efficiency of Rb binding and casein kinase II phosphorylation by the E7 encoded protein of HPV6, compared with E7 protein of HPV16 and 18. These results provide strong experimental support for the hypothesis that the high risk types, in particular their E6 and E7 genes, play an important role in the genesis of human genital cancer and offer insight into the possible mechanisms of E6 and E7 induced carcinogenesis. The E5 protein of bovine papillomavirus type-1, although only 44 amino acids in length, can independently transform rodent fibroblasts. Since it seemed unlikely that E5 has intrinsic enzymatic activity, we investigated the possibility that E5, which is a transmembrane protein, transforms by activating growth factor receptors. E5 was shown to potentiate the activity of co-transfected receptors in a ligand independent manner. Analysis of co-transfected EGF receptors suggested that E5 may transform by interfering with receptor processing.